This invention relates to the improved efficacy of combinations of selected microbicides in selected concentrations and ratios to provide microbicidal activity at lower concentrations and faster response times than would otherwise be observed for the individual microbicides alone. In particular, this invention relates to the improved efficacy of selected microbicide combinations in personal care formulations.
Microbicides are used commercially to prevent the growth of microbes in a variety of loci, such as cooling towers, metal working fluid systems, paints and cosmetics. One of the more important classes of microbicides is 3-isothiazolones, which have achieved commercial success because they are very effective in preventing microbial growth under a wide variety of conditions and in a variety of loci. Another class of commercial microbicides is paraben esters or parabens, that is, alkyl esters of para-hydroxybenzoic acid; these materials are useful in a variety of applications, specifically against yeast and molds. For example, Patent Application WO 96/00060 discloses the use of parabens as a microbicidal preservative in topical therapeutic and cosmetic compositions containing N-acetyl-L-cysteine.
Sometimes the commercial microbicides, used individually, cannot provide effective control of microorganisms even at high use concentrations due to weak activity against certain types of microorganisms. Without effective microbial control, loss of product, inferior product, production time loss, health hazard, and other problems may occur in the loci treated. Combinations of different microbicidal agents are sometimes used to provide overall control of microorganisms in a particular end use environment, for example, in personal care formulations, such as skin care formulations (sunscreens, lotions and creams). However, many of these microbicide combinations are deficient in their overall performance due to a variety of reasons, for example, incompatibility of the individual active ingredients, high use levels of each component required for effective microbicidal activity or limited control of microorganisms due to the reduced lifetime of one of the active ingredients in the combination. There is a need for control of various of microorganisms that does not rely on high use levels of combinations of different microbicidal agents, but provides effective overall control of the microorganisms that is both quick and long lasting.
The problem addressed by the present invention is to overcome deficiencies of previous microbicide combinations by providing a combination of microbicidal agents that is more effective than the individual microbicides used alone or that can be used at overall lower levels while providing efficacy similar to the original individual microbicide levels.
The present invention provides a microbicidal composition comprising (a) a non-halogenated 2-alkyl-3-isothiazolone selected from one or more substituted or unsubstituted 2-(C1-C4)alkyl-3-isothiazolones and (b) a (C1-C7) ester of para-hydroxybenzoic acid, wherein the non-halogenated 2-alkyl-3-isothiazolone and the (C1-C7) ester of para-hydroxybenzoic acid are present in a weight/weight ratio of 1:0.2 to 1:500.
In one embodiment the present invention provides a microbicidal composition as described above wherein the non-halogenated 2-alkyl-3-isothiazolone is 2-methyl-3-isothiazolone and the (C1-C7) ester of para-hydroxybenzoic acid is a mixture of methyl para-hydroxybenzoate and propyl para-hydroxybenzoate.
The present invention further provides a method of inhibiting the growth of microorganisms in a personal care composition comprising introducing to the personal care composition a microorganism-inhibiting amount of a microbicidal composition, the microbicidal composition comprising (a) a non-halogenated 2-alkyl-3-isothiazolone selected from one or more substituted or unsubstituted 2-(C1-C4)alkyl-3-isothiazolones and (b) a (C1-C7) ester of para-hydroxybenzoic acid, wherein the non-halogenated 2-alkyl-3-isothiazolone and the (C1-C7) ester of para-hydroxybenzoic acid are present in a weight/weight ratio of 1:0.2 to 1:500.
In another aspect the present invention provides a personal care composition comprising (a) an ingredient selected from one or more of UV radiation-absorbing agents, surfactants, rheology modifiers or thickeners, fragrances, moisturizers, humectants, emollients, conditioning agents, emulsifiers, antistatic aids, pigments, dyes, tints, colorants, antioxidants, reducing agents and oxidizing agents, and (b) a microbicidal composition as described above.
We have discovered that non-halogenated 2-alkyl-3-isothiazolones may be combined with para-hydroxybenzoic acid esters to provide enhanced microbicidal efficacy at a combined active ingredient level lower than that of the individual 3-isothiazolone or para-hydroxybenzoic acid ester. We have discovered that selected 3-isothiazolones and selected para-hydroxybenzoic acid esters used in specific relative proportions unexpectedly provide the microbicidal compositions of the present invention having enhanced microbicidal efficacy. Preferably the microbicidal compositions are substantially free of halogenated 3-isothiazalone compounds and metal salt stabilizers, such as nitrate or magnesium salts; these xe2x80x9csalt-freexe2x80x9d microbicidal compositions are especially useful to protect personal care compositions against microbial contamination.
As used herein, the following terms have the designated definitions, unless the context clearly indicates otherwise. The term xe2x80x9cmicrobicidexe2x80x9d refers to a compound capable of inhibiting the growth of or controlling the growth of microorganisms at a locus; microbicides include bactericides, fungicides and algaecides. The term xe2x80x9cmicroorganismxe2x80x9d includes, for example, fungi, yeast, bacteria and algae. The term xe2x80x9clocusxe2x80x9d refers to an industrial system or product subject to contamination by microorganisms. xe2x80x9cSalt-freexe2x80x9d means that the composition contains zero or up to 0.5%, preferably zero or up to 0.1%, and more preferably zero or up to 0.01%, of metal salt, based on weight of the composition. Preferably the microbicidal composition is substantially free of halogenated 3-isothiazolone; that is, zero or up to 3%, preferably zero or up to 1% and more preferably zero or up to 0.5%, of halogenated 3-isothiazolone may be present, based on combined weight of halogenated 3-isothiazolone and non-halogenated 2-alkyl-3-isothiazolone.
The following abbreviations are used throughout the specification: cfu=colony forming units, ppm=parts per million by weight (weight/weight), g=gram, mL=milliliter. Unless otherwise specified, ranges listed are to be read as inclusive and combinable, temperatures are in degrees centigrade (xc2x0 C.), and references to percentages (%) are by weight.
Any non-halogenated 3-isothiazolone (NHITA) compound is useful in the compositions of the present invention. Preferably, the NHITA compound is a water soluble compound, that is, having a water solubility typically greater than about 5%. Suitable NHITA compounds include, for example, substituted and unsubstituted non-halogenated 2-(C1-C4)alkyl-3-isothiazolones, where the substituted 3-isothiazolones may contain (C1-C4)alkyl groups at one or both of the 4- and 5- positions of the isothiazolone ring. Specific NHITA compounds include, for example, 2-methyl-3-isothiazolone (MI), 2-ethyl-3-isothiazolone, 2-propyl-3-isothiazolone, 2-isopropyl-3-isothiazolone, 2-butyl-3-isothiazolone (including 2-n-butyl-, 2-isobutyl- and 2-secbutyl- derivatives). Preferably, the NHITA compound is 2-methyl-3-isothiazolone.
Para-hydroxybenzoic acid esters useful in the compositions of the present invention include, for example, the (C1-C7) esters of para-hydroxybenzoic acid, such as methyl, ethyl, propyl (including n-propyl and isopropyl derivatives), butyl (including n-butyl, isobutyl, secbutyl and tertbutyl derivatives), pentyl (including branched and linear variations), hexyl (including branched and linear variations), heptyl and benzyl esters of para-hydroxybenzoic acid. Preferably, the alkyl esters are selected from one or more of methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl para-hydroxybenzoate and benzyl para-hydroxybenzoate (known as paraben esters); more preferably, the parabens esters are a mixture of the methyl para-hydroxybenzoate and propyl para-hydroxybenzoate.
The ratio of non-halogenated 2-alkyl-3-isothiazolone to (C1-C7) ester of para-hydroxybenzoic acid in the compositions of the present invention is typically from 1:0.2 to 1:500, preferably from 1:0.5 to 1:200, more preferably from 1:0.6 to 1:100 and most preferably from 1:1 to 1:60. The concentration of total active ingredient, comprising the non-halogenated 2-alkyl-3-isothiazolone and (C1-C7) ester of para-hydroxybenzoic acid, in the compositions of the present invention, typically ranges from 1 to 75%, preferably from 2 to 50%, more preferably from 5 to 20% and most preferably from 5 to 10%, for xe2x80x9cconcentratexe2x80x9d formulations, based on total weight of the formulated composition; and from 50 to 15,000 ppm, preferably from 100 to 10,000 ppm, more preferably from 150 to 6,000 ppm and most preferably from 300 to 5,000 ppm, in the final xe2x80x9cend usexe2x80x9d formulation, such as a personal care formulation. Typically the concentration of non-halogenated 2-alkyl-3-isothiazolone in final xe2x80x9cend usexe2x80x9d formulations is from 20 to 250 ppm, preferably from 30 to 150 ppm and more preferably from 50 to 100 ppm.
Optionally, other microbicidal agents may be present in the microbicide compositions of the present invention provided that the physical and chemical stability of the composition is substantially unaffected. For example, limited amounts of halogenated 3-isothiazolones, such as, for example, 5-chloro-2-methyl-3-isothiazolone, may be present. Other suitable microbicidal agents that may be present in the microbicide compositions include, for example, 3-iodo-2-propynylbutylcarbamate, 2-bromo-2-nitropropanediol, benzyl alcohol, phenoxyethanol, glutaric dialdehyde, 2-n-octyl-3-isothiazolone, sodium and zinc salts of 2-pyridinethiol-1-oxide, tris(hydroxymethyl)nitromethane, dimethylol-dimethylhydantoin, monomethylol-dimethylhydantoin and benzisothiazolone. Preferably the composition is substantially free of other microbicidal agents; that is, zero or up to 20%, preferably zero or up to 5%, and more preferably zero or up to 1%, of other microbicidal agents may be present, based on the weight of the composition.
Those skilled in the art will recognize that the NHITA and paraben ester components of the present invention may be added to a locus sequentially, simultaneously, or may be combined before being added to the locus.
When the microbicides are combined prior to being added to a locus, the combination is typically provided in the form of a concentrate solution or dispersion; for example, solutions may be based on water-soluble organic solvents, including for example: polyols (alkyleneoxide glycols such as ethylene glycol, diethylene glycol, polyethylene glycols, propylene glycol, dipropylene glycol and polypropylene glycols; alkanediols such as 1,3-butanediol, 1,2-pentanediol, 1,4-pentanediol and 1,5-pentanediol; and alkanetriols such as glycerol); (C1-C4)alkyl esters of acetic acid and propionic acid (such as methyl acetate, ethyl acetate, ethyl propionate and butyl acetate); (C2-C4) alcohols (such as ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, sec-butyl alcohol and tert-butyl alcohol); benzyl alcohol; and phenoxyethanol. Preferably the water-soluble organic solvent is selected from one or more of propylene glycol, dipropylene glycol, 1,3-butanediol, benzyl alcohol and phenoxyethanol. Alternatively, the concentrates may be provided as aqueous dispersions (together with surfactants), aqueous mixtures of the aforementioned water-soluble organic solvents, or as solid formulations containing suitable carrier materials.
When the microbicides are combined prior to being added to a locus, such combination may optionally contain one or more of solvent, thickeners, anti-freeze agents, colorants, dispersants, surfactants, stabilizers, scale inhibitors and anti-corrosion additives.
The microbicidal compositions of the present invention can be used to inhibit the growth of microorganisms by introducing a microbicidally effective amount of the compositions onto, into, or at a locus subject to microbial attack. Suitable loci include, for example: cooling towers; air washers; boilers; mineral slurries; wastewater treatment; ornamental fountains; reverse osmosis filtration; ultrafiltration; ballast water; evaporative condensers; heat exchangers; pulp and paper processing fluids; plastics; emulsions; dispersions; paints; latexes; coatings, such as varnishes; construction products, such as mastics, caulks, and sealants; construction adhesives, such as ceramic adhesives, carpet backing adhesives, and laminating adhesives; industrial or consumer adhesives; photographic chemicals; printing fluids; household products, such as bathroom and kitchen cleaners; cosmetics; toiletries; shampoos; soaps; detergents; industrial cleaners; floor polishes; laundry rinse water; metalworking fluids; conveyor lubricants; hydraulic fluids; leather and leather products; textiles; textile products; wood and wood products, such as plywood, chipboard, flakeboard, laminated beams, oriented strandboard, hardboard, and particleboard; petroleum processing fluids; fuel; oilfield fluids, such as injection water, fracture fluids, and drilling muds; agriculture adjuvant preservation; surfactant preservation; medical devices; diagnostic reagent preservation; food preservation, such as plastic or paper food wrap; pools; and spas.
Preferably, the microbicidal compositions of the present invention are used to inhibit the growth of microorganisms at a locus selected from one or more of emulsions, dispersions, paints, latexes, household products, cosmetics, toiletries, shampoos, soaps, detergents and industrial cleaners. In particular, the microbicidal compositions are useful in personal care applications, such as hair care (for example, shampoo and dyes) and skin care (for example, sunscreens, cosmetics, soaps, lotions and creams) formulations.
The personal care compositions of the present invention, besides comprising the microbicidal combination of a non-halogenated 2-alkyl-3-isothiazolone and a (C1-C7) ester of para-hydroxybenzoic acid, also comprise one or more ingredients selected from UV radiation-absorbing agents, surfactants, rheology modifiers or thickeners, fragrances, moisturizers, humectants, emollients, conditioning agents, emulsifiers, antistatic aids, pigments, dyes, tints, colorants, antioxidants, reducing agents and oxidizing agents.
Suitable UV radiation-absorbing agents (including chemical absorbers and physical blockers) include, for example, oxybenzone, dioxybenzone, sulisobenzone, menthyl anthranilate, para-aminobenzoic acid, amyl para-dimethylaminobenzoic acid, octyl para-dimethylaminobenzoate, ethyl 4-bis(hydroxypropyl)para-aminobenzoate, polyethylene glycol (PEG-25) para-aminobenzoate, ethyl 4-bis(hydroxypropyl)aminobenzoate, diethanolamine para-methyoxycinnamate, 2-ethoxyethyl para-methoxycinnamate, ethylhexyl para-methoxycinnamate, octyl para-methoxycinnamate, isoamyl para-methoxycinnamate, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate, 2-ethylhexyl salicylate, homomenthyl salicylate, glyceryl aminobenzoate, triethanolamine salicylate, digalloyl trioleate, lawsone with dihydroxyacetone, 2-phenylbenzimidazole-5-sulfonic acid, 4-methylbenzylidine camphor, avobenzone, titanium dioxide and zinc oxide. Alternatively, UV radiation-absorbing agents such as triazines, benzotriazoles, vinyl group-containing amides, cinnamic acid amides and sulfonated benzimidazoles may also be used.
Suitable surfactants include, for example, nonionic, anionic, cationic and amphoteric surfactants and mixtures thereof; such as PPG 28 Buteth 35, PEG 75 lanolin, perfluoropolymethyl isopropyl ether, octoxynol-9, PEG-25 hydrogenated castor oil, polyethylene terephthalate, polyethylene glycol 25 glyceryl trioleate, oleth-3 phosphate, PPG-5-ceteth-10 phosphate, PEG-20 methyl glucose ether, glycereth-7-triacetate and N-alkyl substituted lactam (such as N-octyl pyrrolidone).
Suitable thickeners or rheology modifiers include, for example, hydrophobically modified nonionic ethoxylated urethanes, polycarboxylic acid thickeners such as acrylates/steareth-20 methacrylate copolymer, carbomers, acrylates copolymer and acrylates C10-30 alkyl acrylate crosspolymer.
The personal care compositions improved by the method of this invention include, for example:
(a) hair care formulations, including shampoos, hair dyes, hair conditioners, gels, mousses and hair sprays; and
(b) skin care and nail care formulations, including nail coatings, cosmetics, astringents, depilatories, facial make-up formulations, sunscreens and sunblocks, premoistened wipes, hand creams, hand and body soaps, and hand and body lotions.
The cosmetic formulations typically contain water, film forming materials, emulsifiers, softeners, emollients, oils, stabilizers, thickeners, neutralizers, perfume, colorants, pigments and combinations thereof. The sunscreen formulations typically contain UV radiation-absorbing agents, water, film forming materials, emulsifiers, emollients, waterproofing agents, oils, stabilizers, thickeners, preservatives, perfume, colorants, insecticides, humectants and combinations thereof.
Optionally, other additives, such as additional film forming agents, plasticizers, antifoaming agents, leveling aids, excipients, vitamins, natural extracts, proteins, sequestrants, dispersants, antioxidants, suspending agents and solvents may be added to the personal care formulations described above. Suitable solvents include, for example, C1-C12 straight or branched chain alcohols such as ethanol, isopropanol, or propanol; alkyl esters such as ethyl acetate; ketones; and combinations thereof.
Some embodiments of the invention are described in detail in the following Examples. All ratios, parts and percentages are expressed by weight unless otherwise specified, and all reagents used are of good commercial quality unless otherwise specified. Abbreviations used in the Examples and Tables are listed below with the corresponding descriptions:
MI=2-methyl-3-isothiazolone
MP=methyl para-hydroxybenzoate
PP=propyl para-hydroxybenzoate
DU=diazolidinyl urea
IU=imidazolidinyl urea
CFU=colony forming units
SI=synergy index